In parts of the adult brain, proliferating cells continually give rise to new neurons. Adult neurogenesis may be involved in pathological conditions ranging from epilepsy to depression, and neurogenesis in the adult hippocampus may also have physiological significance in long-term memory storage. However, it is unknown if brain activity in the adult is meaningfully coupled to neurogenesis to modulate information storage, or other forms of adaptive plasticity at the cellular level. We have obtained data indicating that indeed, adult neural stem cells directly respond to activity using intrinsic calcium signaling that couples to neurogenesis. We next plan to delineate in vitro the molecular mechanisms involved in this excitation-neurogenesis coupling and the synaptic wiring of newborn neurons, focusing on specific channels and second messengers known to be involved in hippocampal calcium signaling. We will then extend these findings to the in vivo situation, and ultimately explore the behavioral consequences of adult excitation-neurogenesis coupling in intact animals. In the course of this research, Robert Malenka, MD PhD, will be the mentor, and Theo Palmer, PhD, will be a collaborator. Dr. Malenka is a world-renowned synaptic physiologist and psychiatrist with expertise in hippocampal activity-dependent plasticity extending to in vivo manipulations and behavior, and Dr. Palmer is an established neural stem cell expert also at Stanford. In my PhD training with Dr. Richard Tsien, I developed an extensive set of techniques in activity-dependent calcium signaling which can be applied to this new question; at the same time, the research proposed here will provide me with a critical opportunity to gain experience with in vivo manipulations, behavioral analysis, and stem cell techniques essential to my training. Furthermore, carrying out this proposal will allow me to develop an independent research program that can be transitioned to a tenure-track position in a psychiatry department, where I look forward to continuing with 75-80% research and 20-25% patient care, and opportunities to teach and mentor others